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Vol. 19, Issue 9, 3812-3822, September 2008

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RNA-binding Protein HuR Interacts with Thrombomodulin 5'Untranslated Region and Represses Internal Ribosome Entry Site–mediated Translation under IL-1β Treatment

Chiu-Hung Yeh^*, Liang-Yi Hung^*,,, Chin Hsu^,, Shu-Yun Le^||, Pin-Tse Lee^¶, Wan-Lin Liao, Yi-Tseng Lin^#, Wen-Chang Chang^*, and Joseph T. Tseng^*,@

*Department of Pharmacology, ^¶Institute of Basic Medical Sciences, College of Medicine, Institute of Biosignal Transduction, ^@Institute of Bioinformatics, College of Bioscience and Biotechnology, and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan; Graduate Institute of Physiology and Molecular Medicine, Department of Physiology, ^#Graduate Institute of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; and ^||Center for Cancer Research Nanobiology Program, National Cancer Institute (NCI) Center for Cancer Research, NCI, National Institutes of Health, Frederick, MD 21702

Submitted September 24, 2007; Revised June 2, 2008; Accepted June 13, 2008
Monitoring Editor: Carl-Henrik Heldin

Reduction in host-activated protein C levels and resultant microvascular thrombosis highlight the important functional role of protein C anticoagulant system in the pathogenesis of sepsis and septic shock. Thrombomodulin (TM) is a critical factor to activate protein C in mediating the anticoagulation and anti-inflammation effects. However, TM protein content is decreased in inflammation and sepsis, and the mechanism is still not well defined. In this report, we identified that the TM 5' untranslated region (UTR) bearing the internal ribosome entry site (IRES) element controls TM protein expression. Using RNA probe pulldown assay, HuR was demonstrated to interact with the TM 5'UTR. Overexpression of HuR protein inhibited the activity of TM IRES, whereas on the other hand, reducing the HuR protein level reversed this effect. When cells were treated with IL-1β, the IRES activity was suppressed and accompanied by an increased interaction between HuR and TM 5'UTR. In the animal model of sepsis, we found the TM protein expression level to be decreased while concurrently observing the increased interaction between HuR and TM mRNA in liver tissue. In summary, HuR plays an important role in suppression of TM protein synthesis in IL-1β treatment and sepsis.

These authors contributed equally to this work.

Address correspondence to: Joseph T. Tseng (tctseng{at}mail.ncku.edu.tw) or Wen-Chang Chang (wcchang{at}mail.ncku.edu.tw)

Abbreviations used: CLP, cecal ligation and puncture; IRES, internal ribosome entry site; IL-1β, interleukin 1β; TNF-, tumor necrosis factor-; TM, thrombomodulin; 5'UTR, 5' untranslated region.